title: Growth stimulation leads to cellular senescence when the cell cycle is blocked.
abstract: We tested a hypothesis that activation of growth-promoting pathways is required for cellular senescence. In the presence of serum, induction of p21 caused senescence, characterized by beta-Galactosidase staining, cell hypertrophy, increased levels of cyclin D1 and active TOR (target of rapamycin, also known as mTOR). Serum starvation and rapamycin inhibited TOR and prevented the expression of some senescent markers, despite high levels of p21 and cell cycle arrest. In the presence of serum, p21-arrested cells irreversibly lost proliferative potential. In contrast, when cells were arrested by p21 in the absence of serum, they retained the capacity to resume proliferation upon termination of p21 induction. In normal human cells such as WI38 fibroblasts and retinal pigment epithelial (RPE) cells, serum starvation caused quiescence, which was associated with low levels of cyclin D1, inactive TOR and slim-cell morphology. In contrast, cellular senescence with high levels of TOR activity was induced by doxorubicin (DOX), a DNA damaging agent, in the presence of serum. Inhibition of TOR partially prevented senescent phenotype caused by DOX. Thus growth stimulation coupled with cell cycle arrest leads to senescence, whereas quiescence (a condition with inactive TOR) prevents senescence.
authors.affiliation: Oncotarget, Albany, New York, USA.
authors.forename: Zoya N
authors.initials: ZN
authors.lastname: Demidenko
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003114:Colony-Forming Units Assay; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D008954:Models, Biological; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D044967:Serum; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D007544:Isopropyl Thiogalactoside; D004317:Doxorubicin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus